Longitudinal phenotypic study of late-onset retinal degeneration due to a founder variant c.562C>A p.(Pro188Thr) in the C1QTNF5 gene.

ABSTRACT

Background: Late-onset retinal degeneration (L-ORD) is a rare autosomal dominant retinal dystrophy related to C1QTNF5 gene variants.Materials and methods: Twenty-six patients (21-81 years) with L-ORD due to c.562C>A p.(Pro188Thr) with a mean follow-up time of 8 years (range 1-37 years) underwent an extensive ophthalmic work-up.Results: Best-corrected visual acuity (BCVA) and visual fields were maintained up to 50 to 55 years (n = 8), with a gradual decline, but conservation of functional central vision between 55 to 65 years (n = 15), followed by a steep decrease in overall visual function beyond 65 years (n = 9). Classic anterior segment findings in L-ORD of abnormally long, anteriorly inserted lens zonules were absent in most patients (n = 24/26). In contrast, findings of iris transillumination and sphincter pupillae atrophy with poor dilation were novel. Patients presented with three completely different initial fundus phenotypes adjoining pavingstone-like atrophic patches (type 1) (n = 6/20); tiny yellow-white subretinal dots (type 2) (n = 8/20); or larger yellow, thick, round sub-RPE drusenoid deposits (type 3) (n = 4/20). Two patients had a mixed phenotype. Although different in presentation phenotype, patients eventually all progressed to a common panretinal atrophy with diffuse intraretinal pigment migration beyond the age of 65. Progression pace, and thus visual prognosis, differed depending on presentation phenotype. Specifically, type 2 appears to have a more benign course.Conclusions: Phenotypic analysis showed three distinct presenting phenotypes with a considerable intrafamilial variability both in age of onset of clinical signs and in disease progression, with a fair visual potential (>20/40) until the seventh decade.Abbreviations L-ORD Late-onset retinal degeneration; C1QTNF5 complement 1Q tumor necrosis factor 5; OCT Ocular coherence tomography; BCVA Best-corrected visual acuity; RPE Retinal pigment epithelium; ffERG Full-field electroretinography; IRD Inherited retinal dystrophy; CNV Choroidal neovascularization; LAZ Long anteriorly inserted zonules; AMPK AMP-activated protein kinase; IOP Intraocular pressure; cSLO confocal scanning laser ophthalmoscopy; BAF Blue light autofluorescence; NIR-AF Near-infrared autofluorescence; NIR-R Near-infrared reflectance; RF Red-free; SD-OCT Spectral domain ocular coherence tomography; HRR Hardy-Rand-Rittler pseudo-isochromatic plates; AS anterior segment; UBM ultrasound biomicroscopy; PCR Polymerase chain reaction; SNP Single nucleotide polymorphism; VEGF Vascular endothelial growth factor; IZ Interdigitation zone; EZ Ellipsoid zone; ELM External limiting membrane; LP Light perception; AMD Age-related macular degeneration; SFD Sorsby fundus dystrophy.